The present invention relates to biocompatible, antimicrobial compositions that are useful as coatings on medical devices to inhibit attachment and/or growth of microorganisms on the medical device.
Postoperative surgical site infections (SSIs) occur in approximately 2.5% of all patients who undergo surgical procedures. In essentially all cases, some type of medical device is utilized by the surgeon and remains in the patient following surgery. The type of medical device implanted in the human body varies depending on the nature of the operation. It is quite common that some type of suture or other wound closure material or device is utilized. While the body""s immune response normally is successful in preventing microbial infection at the wound site, in the presence of foreign matter, such as the medical device, the probability of infection increases significantly.
Most infections associated with medical device implantation are caused by bacteria. Coagulase negative Staphylococcus species are the primary cause of these infections, accounting for 30-40% of all SSIs. Staphylococcus aureus is involved in 10-20%, Streptococcus species cause 5-10%, and Enterococcus species account for another 10-15%. It is obvious that Gram positive bacteria are the causative infectuous agents in the majority of SSIs relative to medical device implantation. Gram negative bacteria Pseudomonas, E. coli, Enterobacter, and other coliforms) account for 10-20% of these infections, and the remainder are due to yeasts, fungi and anaerobic bacteria.
The primary mode of infection associated with medical device implantation is attachment of microorganisms, e.g. bacteria, to the device, followed by growth and formation of a biofilm on the device. Subsequent release and migration of the microbial contaminant from the biofilm to tissue immediate to and surrounding the device results in a SSI. Once a biofilm is present on a medical device, it is practically impossible to treat the infection without actually removing and replacing the device.
While antimicrobial substances or toxins, i.e. substances which in and of themselves are toxic to microorganisms capable of causing infection at surgical sites, may be added to medical devices, they typically have limitations. Many of the antimicrobial substances are toxic to the patient, while others cause allergic reactions. In addition, certain microorganisms are resistant to such antimicrobial substances due to the development of defense mechanisms that actually destroy the antimicrobial molecule. For example, Penicillinase is produced by Staphylococcus species to break down penicillin.
Oxidized regenerated cellulose (ORC) hemostatic agents have been shown to have broad-spectrum antimicrobial activity due to their pH lowering properties. A general discussion of the in-vitro and in-vivo antimicrobial properties of ORC is found in Dineen, P., xe2x80x9cAntibacterial Activity of Oxidized Regenerated Cellulosexe2x80x9d, SURGERY, Gynecology and Obstetrics, April 1976, Volume 142, number 4. In a related article found in Dineen, P., xe2x80x9cThe Effect of Oxidized Regenerated Cellulose on Experimental Intravascular Infectionxe2x80x9d, SURGERY, November 1977, Volume 82, number 5, it is stated that the mechanism of action of ORC apparently is mediated through its pH effect, because in vitro the antibacterial action can be reduced or eliminated by the use of sodium hydroxide.
In certain coatings used to provide medical devices with bacteria-resistant surfaces, acid-chelating components are reactively bound to a hydrophilic polyurethane prepolymer along with noble metal combinations or antibacterials. It is noted that such noble metals and/or antibacterials are necessary in order for such coatings to provide such antimicrobial effect.
It is important to note that in the example presented above, when ORC is placed in the body, the pH effect is very localized and controlled and results in no adverse effect on the tissue in the immediate or surrounding environments.
In order to provide safe and efficient prevention of infections related to the implantation of medical devices, it would be advantageous to provide an implantable device capable of inhibiting the attachment and/or growth of microorganisms thereto. In order for a medical device to effectively resist microbial attachment and subsequent growth, it must possess an antimicrobial property that is broad spectrum, i.e. it is effective in inhibiting the attachment and/or growth of a large spectrum of microorganisms capable of causing infection.
We unexpectedly have discovered a means to provide such antimicrobial properties to a wide variety of implantable devices through the use of a biocompatible, antimicrobial coating applied to the device. Advantageously, the antimicrobial property can be imparted to the device without significant cost increase or significant alteration of the mechanical properties of the device.
The present invention is directed to compositions containing a biocompatible acid precursor in amounts effective to inhibit microbial attachment and/or growth on a surface of a medical device having the composition applied thereto, to coatings or films prepared from such compositions and to medical devices having the composition applied to a surface thereof Once the coated medical device is placed in the body of a mammal, e.g. a human or animal, the acid precursor in the coating produces acid moieties at concentrations effective to maintain the pH of the coating and/or the tissue area immediate to and adjacent the device at a level effective to inhibit microbial attachment and/or growth on the coated surface of the medical device. The acid precursor may diffuse through the coating and then hydrolyze at the surface of the coated device, or in the immediate vicinity. Alternately, or in combination with the above, upon implantation of the coated device, the acid precursor may first hydrolyze, with the resulting acid diffusing through the coating to the surface to provide the effective pH.